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-Ajay Kumar Singh-Shashi Sharma•Department of Ophthalmology•King George‘s Medical University, Lucknow (INDIA)
ANTIMICROBIALS
LOCAL ANAESTHETICS
ANTINEOPLASTIC DRUGS
ANTIOXIDANTS
ANTI VEGF
ANTIMICROBIAL AGENTS Synthetic as well as naturally obtained drugs that attenuate microorganisms.
CLASSIFICATION:
On the basis of type of organism, they inhibit-
Antibacterial- Penicillins, Aminoglycosides, Fluoroquinolones etc.
Antifungal- Amphotericin B, Fluconazole etc.
Antiviral- Acyclovir, Zidovudine etc.
Antiprotozoal- Metronidazole
Antihelminthic- Albendazole, Niclosamide etc.
On the basis of mechanism of action:
Inhibit cell wall synthesis- Penicillins, Cephalosporins
Cause leakage from cell membrane- Amphotericin B
Inhibit protein synthesis- Tetracyclines, Chloramphenicol
Cause misresding of m-RNA code- Aminoglycosides
Inhibit DNA gyrase- Fluoroquinolones
Interfere with DNA function- Metronidazole, Rifampicin
Interfere with DNA synthesis- Acyclovir, Zidovudin
On the basis of type of action
Primarily bacteriostatic Primarily bactericidal
Sulfonamides Penicillins
Tetracyclines Cephalosporins
Chloramphenicol Aminoglycosides
Fluoroquinolones
Vancomycin
Antibacterials
Used locally (topically and subconjunctivally) in prophylaxis (pre and postoperatively) and treatment of ocular bacterial infections.
Used systemically (orally and intravenously) for the treatment of preseptal/orbital cellulitis
e.g. amoxycillin with clavulanate, , cephalosporin, vancomycin
Can be injected intravitreally for the treatment of endophthalmitis
ANTIBACTERIAL AGENTSPENICILLINS:
Bactericidal
Short half-life
Excreted mainly via kidney; a small fraction via biliary tract
Act by interfering with cell wall synthesis
Most have narrow spectrum, mainly against Gram-positive organisms
Have synergistic action with aminoglycosides
3 major groups:
Penicillins effective against cocci and Gram-positive bacilli
Eg. Benzyl penicillin (non acid stable) and penicillin V (acid stable)
Penicillinase resistant penicillins
Eg. Cloxacillin and flucloxacillin
Extended spectrum penicillins
Aminopenicillins: Ampicillin, Amoxycillin
Carboxypenicillins: Ticarcillin, Carbenicillin
Ureidopenicillins: Piperacillin, Mezlocillin
β- LACTAMASE INHIBITORS:
Clavulanic acid:
Obtained from Streptomyces clavuligerus
Tissue distribution and elimination matches Amoxicillin
Combination- COAMOXYCLAV (Amoxycillin 250/500 mg + clavulanic acid 125 mg)
Sulbactum:
Less potent than clavulanic acid
Oral absorption inconsistent: given parenterally
Tazobactum:
Pharmacokinetics matches Piperacillin (combination- TAZOMAC : Piperacillin 4g + tazobactum 0.5g)
Here comes your footer Page 10
DRUGS SPECTRUM DOSE
Penicillin derivatives
Penicillin Gram-positive organisms, Spirochetes SYSTEMIC- 4-30 million U in 24 divided doses 4-6 hourlyTOPICAL- 0.1 million U/mL (Fortified drops)
Cloxacillin Gram-positive organisms, also penicillinase producing
SYSTEMIC-50-100mg/kg/day oral/i.v. 6 hourly
Ampicillin Gram-positive organisms, H. influenzae, E. coli, Proteus, Salmonella, Shigella
SYSTEMIC-50-100mg/kg/day oral/i.v. 6 hourlyTOPICAL- 10 mg/mL (Fortified drops)INTRAVITREAL- 500 mg/mL
Amoxycillin Gram-positive organisms SYSTEMIC-25-50mg/kg/day oral 8 hourly
CEPHALOSPORINS:
Structure and mode of action similar to penicillins (bactericidal)
Relatively resistant to staphylococcal penicillinase
Patients allergic to penicillin may develop allergy
Intraocular penetration not very good
DRUGS SPECTRUM DOSE
Cephalosporins
1st Generation
Cephalexin Gram-positive organisms, penicillinase producing staphylococci, C.diphtheriae, Clostridia, Actinomyces, E. coli, Klebsiella, Shigella, Salmonella, Proteus, H. influenzae
25-50 mg/kg/day oral 6 hourly
Cephazolin Gram-positive organisms, E. coli, Proteus, H. influenzae
25-50 mg/kg/day i.m./i.v. 8 hourlyTOPICAL-50 mg/mL (Fortified drops)INTRAVITREAL- 2.25 mg in 0.1 mL
2nd Generation
Cefamandole Gram-positive organisms, E. coli, Proteus, H. influenzae
1 gram 4 hourly i.v.TOPICAL- 50 gram/mL (Fortified drops)
Cafaclor Gram-positive organisms, E. coli, Proteus, H. influenzae
25-50 mg/kg/day oral 8 hourly
Cefuroxime Gram-positive and negative organisms, penicillinase-producing N.gonorrhoeae, ampicillin-resistant H. influenzae
30-100 mg/kg/day i.m./i.v. 8-12 hourly
DRUGS SPECTRUM DOSE
3rd Generation
Cefotaxim Aerobic Gram-negative organisms 100-150 mg/kg/day i.m./i.v. 8-12 hourlyTOPICAL- 50 mg/mL (Fortified drops)
Ceftriaxone Aerobic Gram-negative organisms 80-150 mg/kg/day i.v. 8-12 hourly
Cefoperazone Gram-positive organisms, Pseudomonas, Salmonella, Bacteroides fragilis
50-200 mg/kg/day i.m. 8-12 hourly
Ceftazidime Aerobic Gram-negative organisms, Pseudomonas 50-100 mg/kg/day i.v. 8-12 hourlyINTRAVITREAL- 2.25 mg in 0.1 mL
AMINOGLYCOSIDES:
Bactericidal
Broad spectrum of activity against Gram-positive and Gram-negative organisms
Renal and vestibular toxicity
Interfere with neuromuscular conduction- may cause paralysis in Myasthenia gravis patients
Intravitreal injections may cause retinotoxicity
DRUGS SPECTRUM DOSE
Aminoglycosides
Gentamicin Aerobic Gram-negative organisms, Pseudomonas, Proteus, E.coli, Klebsiella
SYSTEMIC- 4-8 mg/kg.day i.m./i.v. 8 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITREAL- 200-400 μg in 0.1 mL
Amikacin Aerobic Gram-negative organisms, gentamicin-resistant organisms
SYSTEMIC- 15-20 mg/kg.day i.m./i.v. 8 hourlyTOPICAL- 0.3% dropsINTRAVITREAL- 400 μg in 0.1 mL
Tobramycin Aerobic Gram-negative organisms, Proteus, Pseudomonas
SYSTEMIC- 6-7.5 mg/kg/day i.m./i.v. 8-12 hourlyTOPICAL- 0.3% drops/ointmentINTRAVITRAL- 150-200 μg/mL
Neomycin most Gram-negative bacilli and some Gram-positive cocci
SYSTEMIC- 4-12 gram/day 6 hourlyTOPICAL- 0.17% drops, 5 mg/gram ointment
Framycetin Activity similar to neomycin TOPICAL- 0.5% drops
TETRACYCLINES:
Broad spectrum antibiotics with bacteriostatic action against both Gram-positive and Gram-negative organisms as well as some fungi, rickettsiae and chlamydiae.
Get deposited in growing bones- not to be used in children and pregnant or lactating mothers
MACROLIDES:
Bacteriostatic agents with narrow spectrum against Gram-positive organisms, Chlamydia and Toxoplasma gondii.
DRUGS SPECTRUM DOSE
Tetracycline and its derivative
Tetracyclin Gram-positive and negative organisms SYSTEMIC-50 mg/kg/day oral 6 hourlyTOPICAL- 1% drops/ointment
Doxycyclin Gram-positive and negative organisms, spirochaetes, rickettsiae, chlamydiae, Mycoplasma, Actinomyces, Entamoeba histolytica
SYSTEMIC- 1.5-2 mg/kg/day oral 12-24 hourly
MacrolidesErythromycin Gram-positive cocci, H.influenzae,
E.coli, Mycoplasma, Salmonella, Chlamydia
SYSTEMIC- 1-4 gram/day oral/i.v. 6 hourlyTOPICAL- 0.5% ointmentINTRAVITREAL- 500 μg/mL
Azithromycin Gram-positive organisms, Chlamydia, Toxoplasma gondii
SYSTEMIC-20-30 mg/kg oral single doseTOPICAL- 1% drops
Vancomycin Gram-positive organisms, staphylococci, MRSA, enterococci, Streptococcus viridans, Clostridium
SYSTEMIC- 2 gram/day 6-12 hourlyTOPICAL- 50 mg/mL (Fortified drops)INTRAVITREAL- 1 mg in 0.1 mL
Combination drugs
Co-trimoxazole (400 mg sulphamethoxazole + 80 mg trimethoprim)
Gram-positive and negative organisms SYSTEMIC-6 mg of trimethoprim equivalent/kg/day oral 12 hourly
GLYCOPEPTIDES:
Very effective against nearly all Gram-positive as well as against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis.
toxic if used topically or subconjunctivally
VANCOMYCIN:
High systemic toxicity
Nephro and ototoxic
Used intravitreally/parenterally for treatment of endophthalmitis
FLUOROQUINOLONES:
Derivatives of nalidixic acid
Broad spectrum agents
1st generation
• active mainly against Gram-negative organisms
• Eg. Norfloxacin, Ciprofloxacin, Ofloxacin, Pefloxacin
2nd generation
• also active against Gram-positive and anaerobe organisms
• Eg. Levofloxacin, Lomefloxacin, Gatifloxacin, Moxifloxacin
Get deposited in growing cartilage- not recommended in children
DRUGS SPECTRUM SYSTEMIC DOSE TOPICAL/ INTRAVITREAL DOSE
Fluoroquinolones
Ciprofloxacin Actinomyces, Nocardia spp., Toxoplasma spp.
Aerobic Gram-negative organisms
15-20 mg/kg/day oral 12 hourly
7-10 mg/kg/day i.v. 12 hourly
TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mL
Norfloxacin Aerobic Gram-negative organisms
10 mg/kg/day oral12 hourly TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mL
Ofloxacin Gram-positive and negative organisms
200-400 mg oral 12 hourly TOPICAL- 0.3% drops/ointmentINTRAVITREAL- 100 μg in 0.1 mL
Levofloxacin Gram-positive and negative organisms
250-750 mg oral/i.v. 24 hourly TOPICAL- 0.5% dropsINTRAVITREAL- 150 μg in 0.1 mL
Gatifloxacin Gram-positive and negative organisms
200-400 mg oral 24 hourly TOPICAL- 0.3%, 0.5% drops,0.3% ointment
Moxifloxacin Gram-positive and negative organisms
200-400 mg oral/i.v. 24 hourly TOPICAL- 0.5% drops/ointment
CHLORAMPHENICOL:
Bacteriostatic agent
Active against bacteria, spirochaetes, rickettsiae, chlamydiae and mycoplasmas
Widest spectrum for superficial ocular infections
Toxic to the corneal epithelium
May lead to blood dyscrasias
SULPHONAMIDES:
Bactriostatic agents
Used against Gram-positive bacteria and Chlamydia.
Eg. Topical 10-30% sulphacetamide- Trachoma
ANTI FUNGALS Classified on the basis of molecular structure
Polyenes Imidazole Triazoles
Amphotericin B Natamycin Ketoconazole
Fluconazole Itraconazole Voriconazole
Polyenes
First effective antifungal used
Bind preferentially to ergosterol in fungal plasma membrane, thereby altering membrane permeability and disruption of fungal cells
Has poor corneal penetration
Used effectively against variety of filamentous fungi Aspergillus, Candida, Histoplasma
Local hypersensitivity and corneal epithelial toxicity may occur
Prolong use may cause renal, bone marrow or CNS toxicity
AMPHOTERICIN B NATAMYCIN
Produced from Streptomycetes nodosus Streptomyces natalenses
Dosage •TOPICAL: 0.075-0.3% drops/hourly •SUBCONUJNCTIVAL: 0.8-1 mg•INTRAVITREAL: 500 μg in 0.1 mL•SYSTEMIC: 1mg/kg in 5% dextrose 4 hourly i.v.*Pretreat with 25mg hydrocortisone
TOPICAL: 5% ophthalmic suspension/hourly interval followed by gradual taperingTopical suspension should be shaken well before use
Indications Aspergillus, Candida, Cryptococcus and mucormycosis
Candida, Histoplasma and Actinomycetes
Considered superior but has to be reconstituted and has low shelf lifeDOC
Easily available in solution form
Trade names Amphocin, Fungizone Natamet, Nataone, NataAid
Clotrimazole
Chlorinated imidazole derivative
Broad antifungal activity more active in treatment of aspergillus infections
DOSAGE:
1% topical ophthalmic drops and ointment
Topical drops are instilled hourly followed by gradual tapering
Ointment is applied 4 times a day
Adverse reactions include ocular irritation and punctate keratopathy
Fluconazole
Most effective against yeast species Candida and Cryptococcus
DOSAGE:
0.3% solution
Every 4 hour interval with gradual tapering
Has faster and deeper penetration
Highly effective in fungal keratitis with deep abscess
Adverse reactions are minimal irritation and transient burning of the eyes
Itraconazole
Shares a similar pharmacokinetic profile with fluconazole
Used in Aspergillius infections, has moderate effects against Candida
DOSAGE:
1% ophthalmic solution
8 times a day is the recommended dosage
Voriconazole
Indicated for use in the treatment of fungal keratitis caused by Aspergillus spp., Fusarium spp.,Candida spp. and Scedosporium apiospermum
PREPARATION:
Lyophilized form
enhances drug stability and solubility
30 mg powder reconstituted with 3 mL to get 10 mg/mL (1% solution)
ADVERSE EFFECTS:
it may cause serious hepatic reactions
ANTI VIRAL DRUGS
Anti viral drugs are activated to triphosphate by viral and cellular thymidine kinases (TK)
This active metabolite then inhibits DNA/RNA replication by competitive inhibition and direct incorporation into viral DNA resulting in chain termination
Oral Acyclovir- 800 mg, 5 times/day
ADVERSE EFFECTS:
Blurring of vision, dizziness, drowsiness, tremors, severe allergic reactions, hematuria
Acyclovir and Ganciclyovir ointment are available for topical use
ACYCLOVIR (3%) GANCICYCLOVIR (0.15%)
Indications • Primary HSV keratitis, dendritic ulcers• Herpes zoster and varicella infections• Acute retinal necrosis syndrome
Adverse effects • Vision blurred,irritation,Punctate keratitis• Conjunctival hyperemia• Erythema of eyelid, SPK• Dry eye, Foreign body sensation
Dosage 5 times a day, followed by tapering
Acyclovir vs Gancicyclovir Ganciclovir ophthalmic gel 0.15% is a new dosage form recently approved by the FDA for the treatment of acute herpetic keratitis (dendritic ulcers). Better penetration than acyclovir with lesser side effects
Trade name ACIVIR OINTMENT® VIRSON GEL®
LOCAL ANAESTHETICS
Topical: (drops/jelly)
E.g. Proparacaine 0.5%, Lignocaine 2%
Uses: applanation tonometry, goniscopy,removal of corneal foreign bodies, removal of sutures, examination of patients, cataract surgery
Adverse effects: toxic to corneal epithelium, rarely allergic reactions
Orbital infiltration:
Peribulbar
Retrobulbar
cause anesthesia and akinesia for intraocular surgery
e.g. Lidocaine 2%, Bupivacaine 0.25%-0.5%
ANTINEOPLASTIC AGENTS These are used in chemotherapy of ocular tumours
some are used to decrease the fibroblastic response in ocular surgeries
CLASSIFICATION:
Alkylating agents:
eg. Carboplatin
Antimetabolites:
eg. Methotrexate, Azathioprine, 5- Fluorouracil
Natural products:
Plant products: eg. Vincristine, Etoposide
Microorganism product: eg. Mitomycin C
DRUG GROUP MECHANISM USED IN DOSES
Carboplatin Alkylating agent-Platinum co-ordination complex
Alkylation of nucleic acid resulting in cross linking/ abnormal base pairing of DNA strands
Ocular tumours 560 mg/m2 BSA (body surface area) i.v.
Vincristine Vinca alkaloids Arrest the cell cycle in mitotic phase by disrupting mitotic spindle
Ocular tumours 1.5 mg/m2 BSA i.v.
Etoposide Epipodophyllotoxins Arrests cells in G2 phase and inhibits DNA topoisomerase II
Ocular tumours 150 mg/m2 BSA i.v.
5-Fluorouracil Antimetabolite-Pyrimidine antagonist
Iinhibition of pyrimidine synthesis
To prevent excessive scarring in postoperative period (eg. pterygium surgery, trabeculectomy)
25 mg/mL topical
Mitomycin C Antibiotic alkylating agent
cross linking of DNA as well as an inhibition of RNA and protein synthesis
After pterygium and glaucoma surgery (trabeculectomy) to reduce scarring and recurrence
Ocular surface neoplasias
0.2-0.5 mg/mL (0.02%-0.05%) solution topical
ANTIOXIDANTS
Oxidative damage plays a major role in development of many ophthalmic conditions; viz.
Senile cataract, age related macular degenerations (ARMD), diabetic retinopathy etc.
Mechanism of oxidative damage:
Free radicals and reactive oxygen species are main culprits
Attack proteins (enzymes), neurotransmitters, nucleic acids, phospholipids, retinal pigment epithelium, lens tissue
Antioxidants react rapidly with free radicals and reactive oxygen species
Act as scavengers for free radicals
INDICATIONS:
Senile cataract
Age related macular degeneration
Diabetic retinopathy
Retinopathy of prematurity
Ischemic ophthalmopathy
Corneal inflammatory disorders
Open angle glaucoma
PREPARATIONS:
Various standardised antioxidant combinations, available in form of capsules; eg.
i) Zn 30mg, Cu 1.5mg, Se 60 μg, Mn 5mg, vit.A 6000 IU, vit.B2 20 mg, vit.C 200 mg, vit.E 60 IU
ii) mixed carotenoids, i.e. α-carotene, β-carotene, cryptoxanthin, leutin, zeaxanthin
Major role of various antioxidant elements:
Zinc: integral part of two endogenous antioxidant enzymes viz. catalase and superoxide dismutase
Copper: cofactor for superoxide dismutase
Selenium: cofactor for glutathione peroxidase
Vitamin C: directly reacts with and scavenges free radicals; major function is protection of lens from oxidative damage
Vitamin E: intercalates into cell membrane and protects cellular constituents against free radicals
Carotenoids: major action is to suppress lipid peroxidation (responsible for generation of free radicals)
Lutein and zeaxanthin: only carotenoids found in the retina and lens of the eye. They help reduce risk of developing age-related cataracts and macular degeneration
Astaxanthin: The most powerful of the carotenoids, by far. Astaxanthin can penetrate into every part of the cell
Newer Drug:
PENTOXIFYLLIN: (TRENTAL®)
Xanthine derivative
Major action: improves blood flow in microcirculation
Mechanism:competitive phosphodiesterase inhibitor
raises intracellular cAMP
inhibits TNF-alpha and leukotriene synthesis reduces inflammation
USES:
Hemorrhagic and ischemic retinal damage,
arteriosclerotic chorioretinal dystrophy,
ischemic optic nerve damage in glaucoma
ANTI VEGF
Anti Vascular Endothelial Growth factors
VEGF stimulates both angiogenesis and increased vascular permeability
Major angiogenic factor implicated in the pathogenesis of neovascular and exudative eye diseases
Anti VEGFs inhibit VEGF and thus evolution of the disease
Wet ARMD Diabetic retinopathy BRVO
ROLE OF ANTI VEGF:
Retinopathy of Prematurity
Eales’ Disease
Refractory post surgical CME
Central serous chorioretinopathy
Trabeculectomy (to modulate wound healing)
Coat’s disease
INDICATIONS IN ANTERIOR SEGMENT:
Neovascular glaucoma
Iris neovascularization
Before keratoplasty to reduce corneal vascularization
PEGAPTANIB RANIBIZUMAB BEVACIZUMAB
TRADE NAME Macugen® Lucentis ® Avastin®
COMPOUND Aptamer Antibody fragmentRhuFab
Full humanized mouseMonoclonal antibody
VEGF BINDING PROPERTY
VEGF-A 165
Selective VEGF-A all forms VEGF-A all forms
DOSE 0.3 mg in 90 μl 0.5mg in 0.05 mL 1.25 mg in 0.05 mL
DURATION OF ACTION
1/6 weeks 1/month 1/3 months
COST Rs 47,000/syringe Rs 56,000/vial Rs 37,000/vial
ADVANTAGES Low immunogenicitySelective action
Longer acting than pegaptanib
cost effectiveLong acting
DISADVANTAGES cost CVS risks HTN, CVS risksRebound macular edema
FUTURE DRUGS…
TOPICAL IMMUNE THERAPY
Relatively new concept
To treat iatrogenic inflammation following any type of intraocular surgery
To make up the decreased levels of ocular immunoglobulins vital for ocular defence system against external infections
WHY REQUIRED:
In immediate postoperative period (≈7 days) there is significant decrease in globulin levels of tears
There is increase in tear secretion following surgeries, resulting in dilution of immunoglobulins
There is physical breach in the continuity of ocular tissue, predisposing to infections
DOSAGE:
Available as:
Topical solution (ASPAC)
0.1% each of IgG and IgA and 0.05% of IgM
1-2 drops 3-4 times/day for 7-14 days
ADVERSE EFFECTS:
Only occassionaly- transient burning sensation, stinging, conjunctival injection, hypersensitivity reactions (rarely)